Abstract
After complete transection of the thoracic spinal segment, neonatal rats exhibit spontaneous locomotor recovery of hindlimbs, but this recovery is not found in adult rats after similar injury. The potential mechanism related to the difference in recovery of neonatal and adult rats remains unknown. In this study, 342 animals were analyzed. The vascular endothelial growth factor (VEGF) level in spinal segments below injury sites was significantly higher in postnatal day 1 rats (P1) compared with 28-day-old adult rats (P28) following a complete T9 transection. VEGF administration in P28 rats with T9 transection significantly improved the functional recovery; by contrast, treatment with VEGF receptor inhibitors in P1 rats with T9 transection slowed down the spontaneous functional recovery. Results showed more neurons reduced in the lumbar spinal cord and worse local neural network reorganization below injury sites in P28 rats than those in P1 rats. Transynaptic tracing with pseudorabies virus and double immunofluorescence analysis indicated that VEGF treatment in P28 rats alleviated the reduced number of neurons and improved their network reorganization. VEGF inhibition in neonates resulted in high neuronal death rate and deteriorated network reorganization. In in vivo studies, T9 transection induced less increase in the number of microglia in the spinal cord in P1 animals than P28 animals. VEGF treatment reduced the increase in microglial cells in P28 animals. VEGF administration in cultured spinal motoneurons prevented lipopolysaccharide (LPS)-induced neuronal death and facilitated neurite growth. Western blots of the samples of lumbar spinal cord after spinal transection and cultured spinal motoneurons showed a lower level of Erk1/2 phosphorylation after the injury or LPS induction compared with that in the control. The phosphorylation level increased after VEGF treatment. In conclusion, VEGF is a critical mediator involved in functional recovery after spinal transection and can be considered a potential target for clinical therapy.
Highlights
Complete spinal cord injury (SCI) causes devastating neuronal destruction, axonal contact disruption, progressive demyelination and, complete dissection of the descending motor control pathways below the injury site
The vascular endothelial growth factor (VEGF) level further decreased in P28 animals 3 days after the surgery, but this decrease was not detected in postnatal day 1 rats (P1) rats (Figure 1C, n = 6, P < 0.05 or 0.01)
Based on the observations that compared with adult rats, neonatal rats following complete transection had a spontaneous locomotor recovery that may be due to intrinsic plasticity in the lumbosacral circuitry below the lesion controlling hindlimb locomotor activity (Yuan et al, 2013) and a significant difference in the expression of VEGF, the purpose of this study was to investigate the beneficial effects of VEGF on spinal neural survival and circuit reconstruction in lumbar enlargement to improve hindlimb movement in rats undergoing complete T9 transection
Summary
Complete spinal cord injury (SCI) causes devastating neuronal destruction, axonal contact disruption, progressive demyelination and, complete dissection of the descending motor control pathways below the injury site. Several studies have provided evidence that spontaneous regeneration through the lesion site may restore the significant recovery of locomotor function in neonatal rats receiving complete spinal cord transection (ST; Hase et al, 2002a,b; Tillakaratne et al, 2010). Some investigators have indicated the lack of signs of regeneration in the transection site by either anterograde or retrograde tracing; this finding indicates that the regaining of some hindlimb functions in neonatal rats may be due to changes in the lumbosacral neuronal circuitry after complete ST, rather than the regeneration of axons across the lesion (Bernstein et al, 1981; Tillakaratne et al, 2010; Yuan et al, 2013). It is necessary to promote neuronal survival and significant functional recovery after SCI
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